Endocannabinoids mediate acute fear adaptation via glutamatergic neurons independently of corticotropin‐releasing hormone signaling

Abstract

Recent evidence showed that the endocannabinoid system plays an important role in the behavioral adaptation of stress and fear responses. In this study, we chose a behavioral paradigm that includes criteria of both fear and stress responses to assess whether the involvement of endocannabinoids in these two processes rely on common mechanisms. To this end, we delivered a footshock and measured the fear response to a subsequently presented novel tone stimulus. First, we exposed different groups of cannabinoid receptor type 1 (CB 1 )-deficient mice (CB 1 2/2) and their wild-type littermates (CB 1 1/1 ) to footshocks of different intensities. Only application of an intense footshock resulted in a sustained fear response to the tone in CB 1 2/2 . Using the intense protocol, we next investigated whether endocannabinoids mediate their effects via an interplay with corticotropin-releasing hormone (CRH) signaling. Pharmacological blockade of CB 1 receptors by rimonabant in mice deficient for the CRH receptor type 1 (CRHR1 2/2 ) or type 2 (CRHR2 2/2 ), and in respective wild-type littermates, resulted in a sustained fear response in all genotypes. This suggests that CRH is not involved in the fear-alleviating effects of CB 1 . As CRHR1 2/2 are known to be severely impaired in stress-induced corticosterone secretion, our observation also implicates that corticosterone is dispensable for CB 1 -mediated acute fear adaptation. Instead, conditional mutants with a specific deletion of CB 1 in principal neurons of the forebrain (CaMK-CB 1 2/2 ), or in cortical glutamatergic neurons (Glu-CB 1 2/2 ), showed a similar phenotype as CB 1 2/2, thus indicating that endocannabinoid-controlled glutamatergic transmission plays an essential role in acute fear adaptation.

Stress response recruits the hippocampal endocannabinoid system for the modulation of fear memory

“…Although the generality of this supposition might be disputed (see, e.g., Jacob et al 2009), it seems consistent with the literature indicating that ECS involvement is task-specific (de Oliveira Alvares et al 2005;Hölter et al 2005;Niyuhire et al 2007). Recently, Kamprath et al (2009) have demonstrated a dependency of endocannabinoid action on the intensity of the footshock used in a fear-conditioning task that associates tone response with previous shock treatment.…”

Genetic Dissection of the Role of Cannabinoid Type-1 Receptors in the Emotional Consequences of Repeated Social Stress in Mice

“…Thus, acute CB 1 receptor blockade immediately before the first recall session (Marsicano et al, 2002;Suzuki et al, 2004;Chhatwal et al, 2005) or the genetic deletion of CB 1 receptors (Marsicano et al, 2002;Kamprath et al, 2006;Dubreucq et al, 2010) delays conditioned freezing extinction, possibly as a consequence of a dysregulation of habituation processes (Kamprath et al, 2006). The use of conditional CB 1 receptor mutants has further suggested that it is the absence of CB 1 receptors from cortical glutamatergic neurons that may be responsible for the phenotype observed in constitutive CB 1 receptor mutants (Kamprath et al, 2009). In the present study, between-session analyses of freezing behaviors and the comparison between the initial freezing responses to the cue in the control (unstressed) groups revealed that CB 1 À/À mice displayed increased fear expression and delayed extinction, compared with CB 1 + / + mice.…”

Biphasic Effects of Cannabinoids in Anxiety Responses: CB1 and GABAB Receptors in the Balance of GABAergic and Glutamatergic Neurotransmission

“…Other studies Jacob et al, 2009;Kamprath et al, 2009) evidenced that the more stressful the experimental procedure is, the more activated the eCB system is, thus, allowing observable differences between CB1 receptordeficient animals and their WT littermates. In reference to this point, our protocol aimed at achieving a biphasic effect.…”